Embolization particulates for occluding a blood vessel

ABSTRACT

Injectable embolization particulates (e.g., particles, microstructures, beads) employed in embolization procedures, for facilitating blood vessel occlusion. Exemplary embolization particulates for occluding a blood vessel include a plurality of embolization beads, each bead having a plurality of outwardly protruding portions, wherein, upon a first one and a second one of the beads accumulating against a boundary of the blood vessel, protruding portions of the first bead are configured to intermesh with protruding portions of the second bead, so as to occlude the blood vessel. Also disclosed are compositions of embolization particulates including a plurality of shaped embolization beads, and methods for embolizing or occluding a blood vessel using embolization particulates or compositions thereof. Embolization particulates have particular shapes for facilitating blood vessel occlusion while preventing or diminishing back flow (reflux) of embolic material, and may be coated or impregnated with therapeutic agents or radioactive isotopes, for increasing desirable therapeutic effects.

RELATED APPLICATION

This application is a Continuation of U.S. patent application Ser. No.15/554,850 filed on Aug. 31, 2017, which claims the benefit to 35 U.S.C.§ 371 national phase application of PCT/IB2016/051167, filed Mar. 2,2016, which claims the benefit of priority under 35 USC 119(e) of U.S.Provisional Patent Application 62/127,036, filed on Mar. 2, 2015entitled “Emobilization Microcatheter and Uses Thereof.” The contents ofthe above referenced applications are incorporated herein by referencein their entirety.

FIELD OF THE INVENTION

The present invention, in some embodiments thereof, relates toinjectable embolization particulates (e.g., particles, microstructures,beads) employed in embolization procedures, for facilitating bloodvessel occlusion. Some embodiments of the present invention furtherrelate to compositions of the disclosed embolization particulates, andto methods for embolizing or occluding a blood vessel using thedisclosed embolization particulates or compositions thereof.

BACKGROUND OF THE INVENTION

The technique of embolization involves the introduction of particlesinto the circulation to occlude blood vessels, for example, so as toeither arrest or prevent hemorrhage, or to cut off blood flow to atissue or an organ. Blood vessel occlusion is desirable for managingvarious diseases and conditions. An embolization procedure is typicallyassociated with an insertion of a catheter or a microcathter (dependingon the size of the target blood vessel) into a blood vessel andinjection of an embolic agent through the catheter/microcatheter. Theembolic agent is chosen, for example, based on the size of the vessel tobe occluded, the desired duration of occlusion, or/and the type ofdisease or condition to be treated (e.g., hypervascular tumors, uterinefibroids, etc.), among other factors. Widely known embolic agents areoils, foam, plug, microspheres. or beads.

A follow-up angiogram may be performed to determine the specificity andcompleteness of an arterial occlusion. Blocking the blood supply to thetissue is intended to result in shrinkage or/and death of the tissue.

Embolization therapy is currently used to treat advanced liver cancer inpatients that are not candidates for liver transplantation or liverresection. and also employed for treating other cancer types. There arecurrently numerous embolic therapies available. Exemplary therapies aretrans-arterial embolization (or TAE), transarterial chemoembolization(TACE), drug eluting bead (DEB) therapy, and trans-arterialradioembolization (TARE).

TAE (also known as bland embolization) utilizes embolic particlesinjected into arteries feeding the tumor to stop blood flow to thetumor, thus causing necrosis. Typically, the embolic particles do notcontain a drug.

TACE involves initial localized injections of a chemotherapeutic drugfollowed immediately by injection of embolic particles to prevent drugreflux and to cause embolization. TACE provides for both embolization(necrosis) of tumor cells and chemotherapy. DEB involvescombining/integrating an (elutable) drug into embolic particles, andsimilar to TACE involves two modes of action. In contrast to TACE, DEBprovides sustained drug release. However, currently available DEBproducts show in-vitro rapid release (i.e., within hours) of the drugfrom the embolic particles. Also, current DEB therapy utilizes biostableparticles, thereby precluding re-treatment. Embolic therapies are notcurative, however, in most therapeutic situations, a single therapydelays tumor progression.

Trans-arterial radioembolization (TARE) involves (injective)administration of radioactively labeled microspheres into a bloodvessel. The injected microspheres emit radiation to surrounding tissueswhich then undergo necrosis.

In spite of known teachings and practices in the field and art of theinvention, there is an on-going need for developing new and improvedinjectable embolization particulates (e.g., particles, microstructures,beads), compositions thereof, and methods for using such in embolizationprocedures.

SUMMARY OF THE INVENTION

The present invention, in some embodiments thereof, relates toinjectable embolization particulates (e.g., particles, microstructures,beads) employed in embolization procedures, for facilitating bloodvessel occlusion. Some embodiments of the present invention furtherrelate to compositions of the disclosed embolization particulatesincluding a plurality of shaped embolization beads, and to methods forembolizing or occluding a blood vessel using the disclosed embolizationparticulates or compositions thereof.

According to an aspect of some embodiments of the present invention,there is provided embolization particulates suitable for occluding ablood vessel, the embolization particulates comprising: a plurality ofembolization beads, each of the embolization beads comprises: aplurality of outwardly protruding portions, wherein, upon a first oneand a second one of the embolization beads accumulating against aboundary of the small blood vessel, the protruding portions of the firstembolization bead are configured to intermesh with the protrudingportions of the second embolization bead, so as to occlude the bloodvessel.

According to an aspect of some embodiments of the present invention,there is provided an embolization bead suitable for occluding a bloodvessel, the embolization bead comprising: a plurality of outwardlyprotruding portions, wherein, upon a first one and a second one of theembolization beads accumulating against a boundary of the small bloodvessel, the protruding portions of the first embolization bead areconfigured to intermesh with the protruding portions of the secondembolization bead, so as to occlude the blood vessel.

According to some embodiments of the invention, the embolization beadsare configured to resist or/and dissipate forces generated by, ororiginating from, fluid flow during an embolization procedure. Accordingto some embodiments of the invention, at least one of the outwardlyprotruding portions is hydrodynamically shaped to facilitate laminaror/and unhindered flow there around and to diminish impact of incomingfluid flow directed thereto.

According to some embodiments of the invention, the embolization beadshave three outwardly protruding portions. According to some embodimentsof the invention, the embolization beads have a tetrapod-like shape.According to some embodiments of the invention, at least one of theoutwardly protruding portions has a tetrahedron or tetrahedron-likeshape. According to some embodiments of the invention, at least one ofthe outwardly protruding portions includes at least one concavity.According to some embodiments of the invention, at least one of theoutwardly protruding portions includes at least one hole passing throughthe outwardly protruding portion. According to some embodiments of theinvention, at least one concavity or/and the hole is filled with atherapeutic agent.

According to some embodiments of the invention, the embolization beadsare prepared from a glass, a metal, a polymer, or a combination thereof.According to some embodiments of the invention, the embolization beadshave a diameter in a range of between about 5 micrometers and about 500micrometers, or in a range of between about 5 micrometers and about 100micrometers, wherein the diameter is measured between external surfacesof two opposing protruding portions of one of the embolization beads.

According to an aspect of some embodiments of the present invention,there is provided a composition comprising: the embolizationparticulates, and a pharmaceutically acceptable excipient or carrier.According to some embodiments of the invention, the composition furthercomprises a contrasting agent or a therapeutic agent. According to someembodiments of the invention, the contrasting agent is selected from thegroup consisting of tantalum, tantalum oxide, and barium sulfate.According to some embodiments of the invention, the therapeutic agent isa chemotherapeutic agent.

According to an aspect of some embodiments of the present invention,there is provided a method for embolizing or occluding a blood vessel ina subject, the method comprising: injecting into the blood vessel asufficient amount of the embolization particulates, or of a compositionthereof, thereby allowing the embolization beads to aggregate into achosen aggregated structure prior to or/and during embolization.According to some embodiments of the invention, the blood vessel feeds atumor or an arteriovenous malformation.

According to an aspect of some embodiments of the present invention,there is provided the embolization particulates, or a compositionthereof, for use in embolizing a blood vessel feeding a tumor or anarteriovenous malformation.

According to an aspect of some embodiments of the present invention,there is provided a method of treating a disease or disorder that maybenefit from occluding a blood vessel feeding an organ associated withthe disease or disorder, the method comprising: injecting into the bloodvessel a sufficient amount of the embolization particulates, or of acomposition thereof. According to some embodiments of the invention, inthe method, the disease or disorder is selected from: cancer, anarteriovenous malformation, and hemorrhage.

According to an aspect of some embodiments of the present invention,there is provided the embolization particulates, or a compositionthereof, for use in treating a disease or disorder that may benefit fromoccluding a blood vessel feeding an organ associated with the disease ordisorder. According to some embodiments of the invention, the disease ordisorder is selected from: cancer, arteriovenous malformations, andhemorrhage.

Unless otherwise defined, all technical or/and scientific terms usedherein have the same meaning as commonly understood by one of ordinaryskill in the art to which the invention pertains. Although methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of embodiments of the invention, exemplarymethods or/and materials are described below. In case of conflict, thepatent specification, including definitions, will control. In addition,the materials, methods, and examples are illustrative only and are notintended to be necessarily limiting.

BRIEF DESCRIPTION OF THE DRAWINGS

Some embodiments of the invention are herein described, by way ofexample only, with reference to the accompanying drawings. With specificreference now to the drawings in detail, it is stressed that theparticulars shown are by way of example and for purposes of illustrativediscussion of embodiments of the invention. In this regard, thedescription taken with the drawings makes apparent to those skilled inthe art how embodiments of the invention may be practiced.

In the drawings:

FIG. 1 is a schematic perspective view of an exemplary embodiment of anembolization bead having three protruding portions extending from thecenter of the bead, in accordance with some embodiments of theinvention;

FIG. 2 is a schematic perspective view of an exemplary embodiment ofembolization particulates as an aggregation of a plurality of theembolization bead of FIG. 1, particularly highlighting intermeshing(engaging) of protruding portions of several embolization beads, inaccordance with some embodiments of the invention;

FIG. 3 is a schematic perspective view of an exemplary embodiment of anembolization bead having four protruding portions, each two protrudingportions extending from opposite sides of a bead end, in accordance withsome embodiments of the invention;

FIG. 4 is a schematic perspective view of an exemplary embodiment ofembolization particulates as an aggregation of a plurality of theembolization bead of FIG. 3, particularly highlighting intermeshing(engaging) of protruding portions of several embolization beads, inaccordance with some embodiments of the invention; and

FIG. 5 is a schematic presentation of an exemplary suspension ofembolization particulates (as embolization beads of FIGS. 1 and 2),following injection into a blood vessel (e.g., a hepatic artery) feedinga tumor within the liver, and engaging to form a dense aggregatedstructure before or/and during an embolization process, so as to form anembolus within the blood vessel, thereby occluding the blood vessel, inaccordance with some embodiments of the invention.

DESCRIPTION OF SPECIFIC EMBODIMENTS OF THE INVENTION

The present invention, in some embodiments thereof, relates toinjectable embolization particulates (e.g., particles, microstructures,beads) employed in embolization procedures, for facilitating bloodvessel occlusion. Some embodiments of the present invention furtherrelate to compositions of the disclosed embolization particulatesincluding a plurality of shaped embolization beads, and to methods forembolizing or occluding a blood vessel using the disclosed embolizationparticulates or compositions thereof.

There is still a need to prevent, or at least diminish, possibility ofnon-target embolization or/and non-target deposition of embolizationparticulates (particles, microstructures, beads) which can adverselyaffect non-target locations or/and organs of a subject. Such undesirablenon-target embolization or/and particulate deposition may occur byinfiltration of embolization particulates from a target embolizationsite to a non-target location, for example, via body vasculature or/andabnormal shunts.

A possible way to prevent, or at least diminish, such undesirable sideeffects from occurring during embolization procedures, is to developmeans which enable embolization particulates, for example, via theirinherent characteristics and behavior, to aggregate (i.e., gather,collect, or combine together) under local conditions (such as flow rate,flow pressure, among other possible conditions) during an embolizationprocess. Accordingly, it may be advantageous to provide new and improvedvascular embolic materials, such as embolization particulates (e.g., inthe form of particles, microstructures, beads), which may facilitatesafer and more efficient occlusion of a blood vessel.

For example, according to some embodiments of the disclosed invention,the embolization particulates, for example, in the form of beads, arecharacterizable by a particular shape that may advantageously facilitateblood vessel occlusion while preventing, or at least diminishing, backflow (i.e., reflux) of embolic material. According to some embodimentsof the invention, the embolization particulates, for example, in theform of beads, may be coated or impregnated with a therapeutic agent, orwith a radioactive isotope, for increasing one or more desirabletherapeutic effects.

The terms “embolization” and “embolizing” are herein used in conjunctionwith the terms “embolization material” and “embolization therapy”, andrefer to a process wherein a medicinal substance or material injectedinto a blood vessel hardens, fills, plugs, or/and occludes the bloodvessel or/and encourages clot formation so that blood flow through thevessel ceases. Blood vessel embolization is useful inpreventing/controlling bleeding (e.g., organ bleeding, gastrointestinalbleeding, vascular bleeding, bleeding associated with an aneurysm), oras a treatment of a disease (e.g., cancers) by preventing its bloodsupply.

The terms “aggregation” and “aggregated” are herein used in conjunctionwith the term “aggregated structure”, and refer to a process wherein aparticulate mass (e.g., in a form of infusion suspension of beads)assembles into a concentrated depot, being more concentrated or/anddense than concentration/density of the infusion suspension at exit ofdistal outlet (infusion opening) of the embolization catheter. Such aparticulate mass (concentrated depot) is characterized by at least someof its particles physically (mechanically) or/and chemicallyinterconnecting among themselves. In some embodiments of the invention,particle (inter-particle) aggregation may be considered as a preliminarystage before creation of a local emboli in a blood vessel. In someembodiments, the unique shape or/and weight distribution in a bead,according to embodiments of the invention, improves its inherent abilityto resist aggregation or/and concertation at a too early stage of theembolization delivery process (e.g., close to distal outlet of theembolization catheter or/and at relatively high blood flow rate), sothat a farther distal arterial occlusion can be achieved. Optionally,additionally or alternatively, the unique shape or/and weightdistribution in a bead, according to embodiments of the invention,improves its inherent ability to increase likelihood, strength, density,or/and concertation of a final aggregation in a mature stage of theembolization delivery process (e.g., relatively distant from distaloutlet of the embolization catheter or/and at relatively low blood flowrate), in order to diminish likelihood/quantity of beads (particles)non-target deposition phenomenon.

The term “bead” is herein used in conjunction with “particle” or“particulate”, and refers to a substance, for example, in the form of aminute portion or a fragment of material, that may be formed from avariety of materials (e.g., a glass, a polymer, a metal), and havecharacteristic sizes (lengths, widths, diameters) in an exemplary rangeof between about 10 microns (micrometers) and about 1,000 microns(micrometers), and may be suitable for medical applications (e.g.,occluding a blood vessel), for example, for delivery as a suspendedmaterial in an infusion suspension.

An aspect of some embodiments of the invention is provision ofembolization particulates (in a form of particles, microstructures, orbeads) suitable for occluding a blood vessel. In exemplary embodiments,the embolization particulates include a plurality of embolization beads,with each of the embolization bead having a plurality of outwardlyprotruding portions, wherein, upon a first one and a second one of theembolization beads accumulating against a boundary of the small bloodvessel, the protruding portions of the first embolization bead areconfigured to intermesh with the protruding portions of the secondembolization bead, so as to occlude the blood vessel.

According to an aspect of some embodiments of the present invention,there is provided an embolization bead suitable for occluding a bloodvessel, the embolization bead comprising: a plurality of outwardlyprotruding portions, wherein, upon a first one and a second one of theembolization beads accumulating against a boundary of the small bloodvessel, the protruding portions of the first embolization bead areconfigured to intermesh with the protruding portions of the secondembolization bead, so as to occlude the blood vessel.

An aspect of some embodiments of the invention is provision of acomposition including the embolization particulates and apharmaceutically acceptable excipient or carrier.

An aspect of some embodiments of the invention is provision of a methodfor embolizing or occluding a blood vessel in a subject, the methodincluding: injecting into the blood vessel a sufficient amount of theembolization particulates, or of a composition thereof, thereby allowingthe embolization beads to aggregate into a chosen aggregated structureprior to or/and during embolization. An aspect of some embodiments ofthe invention is provision of a method of treating a disease or disorderthat may benefit from occluding a blood vessel feeding an organassociated with the disease or disorder, the method including: injectinginto the blood vessel a sufficient amount of the embolizationparticulates, or of a composition thereof. An aspect of some embodimentsof the invention is provision of the embolization particulates, or acomposition thereof, for use in treating a disease or disorder that maybenefit from occluding a blood vessel feeding an organ associated withthe disease or disorder.

The preceding aspects of exemplary embodiments of the present invention,and characteristics and features thereof, are better understood withreference to the following illustrative description and accompanyingdrawings. Throughout the following illustrative description andaccompanying drawings, same reference notation and terminology (i.e.,numbers, letters, symbols) are consistently used and refer to samestructures, components, elements, steps or procedures, or/and features.

It is to be understood that the invention is not necessarily limited inits application to particular details of construction of theembolization particulates (or embolization beads thereof), or to anyparticular sequential ordering of method steps or procedures, set forthin the following illustrative description. The invention is capable ofother embodiments or of being practiced or carried out in various ways.For example, the following exemplary embodiments may be described in thecontext of exemplary embolization procedures for ease of description andunderstanding. However, the invention may be adapted to various clinicalapplications without departing from the overall scope of the invention,for example, any local injected deposition of a pharmaceutical ornon-pharmaceutical particulates within a bodily lumen.

Morphological/Structural Characteristics, Properties, and Features ofthe Embolization Particulates (Beads)

In exemplary embodiments, the embolization beads of the inventioninclude a plurality of outwardly protruding portions, wherein outwardlyprotruding portions of a first bead are configured to intermesh withoutwardly protruding portions of a second bead. The beads may havevarious shapes, as long as the beads are capable of intermeshing witheach other and block blood flow. In exemplary embodiments, the beads maybe symmetric or asymmetric. In exemplary embodiments, the embolizationbead is having two or more, three or more, four or more, five or more,or six or more protruding portions. In exemplary embodiments, the beadsprotruding portions may extend from the central portion of the bead. Inexemplary embodiments, the beads have a spherical body and theprotruding portions may extend from the central spherical portion of thebead. In exemplary embodiments, the beads have a body with an elongatedshape and the protruding portions may extend from any portion of thebead body. In exemplary embodiments, the embolization beads have atetrapod-like shape. In exemplary embodiments, at least one of theoutwardly protruding portions has a multi-faced type shape, for example,a tetrahedron (tetrahedral) or tetrahedron-like (tetrahedral-like)shape. In exemplary embodiments, at least one of the outwardlyprotruding portions includes at least one concavity. In exemplaryembodiments, at least one of the outwardly protruding portions includesat least one hole passing through the outwardly protruding portion.

Reference is now made to the drawings. FIG. 1 schematically illustratesa perspective view of an exemplary embolization bead 200 havingexemplary bead protruding portions 201. FIG. 2 schematically illustratesa perspective view of an exemplary embodiment of embolizationparticulates, for example, as an aggregated structure 100 of a pluralityof exemplary embolization beads 200 (of FIG. 1), particularlyhighlighting intermeshing (engaging) of embolization bead protrudingportions 201.

In exemplary embodiments, embolization bead 200 is configured forcreating an embolus during an embolization procedure, and includes aplurality of outwardly protruding portions 201. Embolization bead 200may have a substantially spherical body, for example, spherical body 202shown in FIGS. 1 and 2, and the outwardly protruding portions 201 mayextend from the spherical body 202. In FIGS. 1 and 2, embolization beads200 are illustrated having three protruding portions 201, but may have adifferent number of protruding portions (e.g., two, or four, or moreprotruding portions).

In exemplary embodiments, during the course of injecting the beadswithin a blood vessel and prior to accumulation of a plurality of thebeads into an aggregated structure, such as aggregated structure 100, atleast one of the outwardly protruding portion 201 is hydrodynamicallyshaped to facilitate laminar or/and unhindered flow there around and todiminish impact of incoming fluid flow directed thereto.

In exemplary embodiments, embolization bead 200 is also configured,based on its design and dimensions, such that whereupon at least a firstand a second thereof, accumulating against a boundary of a target bodilypart within a small blood vessel, for example, feeding a target bodilypart, the protruding portions of a first embolization bead will have anincreased probability to intermesh with the protruding portions of asecond embolization bead (as shown, in an exemplary non-limiting manner,in FIGS. 2 and 5), optionally particularly at low (e.g., close to null)blood flow rates.

In some embodiments, aggregated structure 100 or/and embolization bead200 is further configured to resist or/and dissipate forces generated byor originating from fluid flow during the embolization procedure.

In exemplary embodiments, embolization bead 200 has, or is similar atleast in part to, a tetrapod-like shape. Optionally, at least oneoutwardly protruding portion 201 has a multi-faced type shape, forexample, a tetrahedron (tetrahedral) or tetrahedron-like(tetrahedral-like) shape. Optionally, at least one outwardly protrudingportion 201 includes at least one concavity or/and at least one holepassing therethrough the outwardly protruding portion, which,optionally, is filled with a pharmaceutical agent.

FIG. 3 schematically illustrates a perspective view of an exemplaryembolization bead 300 having exemplary bead protruding portions 301.FIG. 4 schematically illustrates a perspective view of an exemplaryembodiment of embolization particulates, for example, as a aggregatedstructure 400 of a plurality of exemplary embolization beads 300,particularly highlighting intermeshing (engaging) of embolization beadprotruding portions 301.

In exemplary embodiments, embolization bead 300 is configured forcreating an embolus during an embolization procedure, and includes aplurality of outwardly protruding portions 301. Embolization bead 300includes a first bead end 303, a second bead end 304, and a bead body302 extending between the first bead end 303 and the second bead end304. Two outwardly protruding portions 301 oppositely extend from thefirst bead end 303, and two outwardly protruding portions 301 oppositelyextend from the second bead end 304. Embolization beads 300 areillustrated having four protruding portions, but may also have adifferent number of protruding portions (e.g., two, three, five, or moreprotruding portions). Protruding portions 301 of embolization bead 300,extending from the first bead end 303 may be disposed to form any anglein a range of between about 180 degrees and about 0 degrees with respectto protruding portions 301, extending from the second bead end 304.

Embolization bead 300 is also configured, based on its design anddimensions, such that whereupon at least a first and a second thereof,accumulating against a boundary of a target bodily part within a smallblood vessel, feeding the target bodily part, the protruding portions ofthe first embolization bead shall have an increased probability tointermesh with the protruding portions of the second embolization bead(as shown, for demonstrative purposes only, in FIGS. 4 and 5).

In some embodiments, embolization bead 300 is further configured toresist or/and dissipate forces generated by or originating from fluidflow during the embolization procedure. In exemplary embodiments, atleast one outwardly protruding portion 301 has a multi-faced type shape,for example, a tetrahedron (tetrahedral) or tetrahedron-like(tetrahedral-like) shape. Optionally, at least one outwardly protrudingportion 301 includes at least one concavity or/and at least one holepassing therethrough the outwardly protruding portion, which,optionally, is filled with a pharmaceutical agent.

In exemplary embodiments, the embolization beads may be prepared invarious sizes. The embolization bead diameter sizes (when measured toextend between two opposite protrusions) may vary and range between 10microns (μm) and 1,500 microns, between 10 microns and 1,200 microns,between 10 microns and 1,000 microns, between 100 microns and 900microns, between 10 microns and 500 microns, between 10 microns and 100microns, between 10 microns and 50 microns, between 50 microns and 100microns, between 100 microns and 300 microns, between 300 microns and500 microns, between 500 microns and 700 microns, or between 700 micronsand 900 microns.

The size and shape of the embolization beads may be measured by anymethod known in the art. For example, microscopic equipment (such as,Leica DM IRB (Leica) microscope equipped by Evolution MP Color CCDCamera (Media Cybernatics)) may be used. The analysis of size may beperformed by Image Pro Plus™ (Media Cybernatics). An electron microscope(such as, scanning electron microscope (SEM)) to obtain a sample'ssurface topography and composition may be used.

In exemplary embodiments, the embolization beads are prepared from amaterial such as, but not limited to, a polymer, a metal, a glass, aceramic material or any combination thereof. When a metal is used forthe preparation of the embolization beads, visualization of the embolicmaterial under X-ray radiation may be facilitated. Exemplary glassembolization beads are, without limitation, silicon dioxide (SiO2),sodium oxide (Na2O), sodium carbonate (Na2CO3), calcium oxide (CaO), orany combination thereof. Exemplary polymers suitable for implementingembodiments of the invention include, without limitation, polyvinylalcohol (PVA), polytetrafluoroethylene (PTFE), carboxymethyl chitosan(CCN), carboxymethyl cellulose (CMC),2-acrylamido-2-methyl-1-1-propane-sulphonoc acid (AMPS),poly(lactide-co-glycolide) (PLCG), poly(L-lactic acid) (PLLA),trisacrylgelatin having a coating of collagen, or any combinationthereof. The polymer used may be chosen to have an appropriate molecularweight. In an exemplary embodiment, and when PVA is the polymer ofchoice, the PVA may have a molecular weight within the range of about50,000 Da and about 300,000 Da. Suitable metals include, withoutlimitation, silver, gold, palladium, platinum, tantalum (e.g. tantalumoxide), tungsten, iridium, titanium, magnesium, Strontium, Zinc,Lanthanum, barium (e.g. barium sulfate), and stainless steel. In anexemplary embodiment, a metal that may be used in preparing theembolization beads may include, without limitation, TiO2, Pt or amixture thereof. In a further exemplary embodiment, the glassembolization beads may be made from a combination of metals and glassand may include one or more of: zinc (e.g., ZnO), Lanthanum (e.g.,La3O2), Titanium (e.g., TiO2), Magnesium (e.g., MgO), Strontium (e.g.,SrO) and sodium (e.g., Na2O).

In exemplary embodiments, the embolization beads have a weight that varyand depend on the material used for producing the bead. The embolizationbead weight may be uniform within the entire bead, or may be non-uniformhaving a center-of-mass not necessarily same as geometric center.Non-uniform embolization bead weight may be controlled or produced bycombining at least two materials each having a different weight andproducing the beads to include those material in a non-homogenousfashion.

In exemplary embodiments, and in order to further enhance thetherapeutic effect (i.e. treating cancer), the embolization beads mayalso include an isotope, thus allowing delivery of β-ray or/and γ-ray.Suitable isotopes that may be incorporated or impregnated to theembolization beads of the invention, include, without limitation,yttrium-90 (Y90), rhenium-188 (¹⁸⁸Re), ⁹⁹mTc, ³²P, ¹⁶⁶Ho, ¹⁰⁹Pb, ¹⁴⁰La¹⁵³Sm, ¹⁶⁵Dy, and ¹⁶⁹Er.

According to further embodiments, and in order to further enhance thetherapeutic effect (e.g., in treating cancer), the embolization beadsmay also include a therapeutic agent. Suitable exemplary therapeuticagents that may be incorporated to the embolization beads of theinvention, include, without limitation, a chemotherapeutic agent, apeptide or polypeptide or any other chemical moiety or entity having atherapeutic effect. An exemplary chemotherapeutics that may beincorporated into the embolization beads of the invention, include, forexample, paclitaxel, doxorubicin, nemorubicin hydrochloride (aderivative of doxorubicin).

Methods of Producing/Manufacturing the Embolization Particulates (Beads)

An aspect of some embodiments of the present invention relates to amethod for producing embolization beads according to the embodiments ofthe invention.

The method includes homogenously admixing together the components fromwhich the embolization beads are to be prepared and pouring a liquidmixture to a premade scaffold or mold. The method further includes,removing the molded particulates.

In an exemplary embodiment, and when the embolization beads are preparedfrom metals, or glass or a combination thereof, the process forpreparing the embolization beads include, weighing and preparing ahomogenous mixture of powders and melting the powders to form thedesired composition. The purity of each raw material is, for example,greater than 90%. After either dry or wet mixing of the powders toachieve a homogeneous mixture, the mixture may be placed for melting(e.g., in a platinum crucible). The crucibles containing the powderedbatch are heated to 1500° to 1600° C., depending upon the composition,by a furnace.

In this temperature range, the batch melts to form a liquid which isstirred several times to decrease its chemical heterogeneity. The meltshould remain at 1500° to 1600° C. until all solid material in the batchis totally dissolved (usually 2-5 hours being sufficient). When meltingand stirring is complete, the crucible is removed from the furnace andthe melt is quickly quenched to a glass by pouring the melt onto a coldmold or scaffold.

The final step is to examine a representative sample of the embolizationbeads in a scanning electron microscope to evaluate the size range andshape of the beads. A composition of the embolization beads can bechecked by energy dispersive x-ray analysis to confirm that there is nochemical contamination. The embolization beads are packaged dry in cleancontainers and sterilized (for example, using 30 kGy gamma irradiation).

In exemplary embodiments, the obtained embolization beads are treated toincorporate a therapeutic agent. The embolization beads in accordancewith this embodiment act as carriers of the therapeutic agent. Thetherapeutic agent may be incorporated to the embolization beads of theinvention, in any method known in the art. The therapeutic agent may beincluded within holes formed in the embolization beads or withinconcavity shapes based on the surface of the protruding portions.

Methods for coating the embolization beads with a therapeutic agentinclude, without limitation, immersion coating, spray coating, and spincoat administration. Immersion coating of therapeutic agent includesimpregnating surface of interest of the embolization beads with thetherapeutic agent.

For example, coating may be performed by dissolving the therapeuticagent at a desired concentration that represents clinically applicabledoses, admixing the therapeutic agent with the embolization beads andincubating those substances for a period of from a few minutes to a fewhours. Drug release may be evaluated following incubation in an aqueoussolution (Phosphate Buffer Saline (PBS)) or human plasma from humansubjects for a few days.

Methods of Using the Embolization Particulates (Beads)

According to an aspect of the invention, there is provided a method forembolizing or occluding a blood vessel in a subject in need thereof, themethod including injecting into the blood vessel a sufficient amount ofembolization beads of the invention, thereby allowing the embolizationbeads to aggregate into an aggregated structure prior to or/and duringembolization.

According to yet another aspect of the invention, there is provided amethod of treating a disease or disorder that may benefit from occludinga blood vessel feeding an organ associated with the disease or disorder,the method including injecting into the blood vessel a sufficient amountof embolization beads of the invention.

As used herein, the term “embolizing” as used in conjunction with theterm “occluding” refers to creating an embolus or clot within a bloodvessel.

As used herein, the term “treating” encompasses substantiallyameliorating, relieving, alleviating and preventing symptoms of thedisease in a patient in need thereof.

As used herein, the term “injecting” is interchangeable with the tern“administering” and refers to the delivery of a suspension of thedisclosed embolization beads within a blood vessel.

The embolization beads are particularly useful in occluding small bloodvessels (such as capillaries). The embolization beads are useful totreat any disease condition or illness which may benefit, abolished, orablated by colluding a blood vessel within the body or that feeds thediseased or afflicted body organ.

The embolization beads may be used in conjunction with a transarterialchemoembolization (TACE), drug eluting bead (DEB) therapy andradio-embolization. As used herein the term “a disease or disorder thatmay benefit from occluding a blood vessel feeding an organ associatedwith the disease or disorder” refers to any disease, disorder, orcondition that may be treated with embolization material to abolish orrelief symptoms associated with the disease, disorder, or condition. Theterm is interchangeable with the term “a disease or disorder amenable toan embolization therapy”.

In exemplary embodiments, the embolization beads may be used to treatangiogenesis-dependent diseases (i.e., those diseases which require orinduce vascular growth). Amongst such angiogenesis-dependent diseasesthe most prominent is cancer. Suitable cancers include, withoutlimitation, a cancer that has spread (metastasized) to the liver from aprimary tumor elsewhere (e.g., colorectal cancer, breast cancer, lungcancer and neuroendocrine tumors), cancer originating in the liver (suchas hepatocellular carcinoma and cholangiocarcinoma), renal tumors(benign and malignant), tumor within the uterine (e.g., uterinefibroid), brain, central nervous system, kidneys, gall bladders, headand neck, oral cavity, thyroid, skin, mucous membranes, glandularorgans, blood vessels, bone tissues, lymph nodes, lungs, esophagus,stomach, lacteal glands, pancreas, eyes, nasopharynge, womb, ovaries,endometrium, cervix, prostate gland, bladders, colon and rectum. Forexample, metastatic colorectal cancer in the liver and hepatocellularcarcinoma are the cancers most often considered for radioembolizationtreatment. In exemplary embodiments, the embolization beads are used toprevent/control bleeding (e.g., organ bleeding, gastrointestinalbleeding, vascular bleeding, bleeding associated with an aneurysm). Forexample, the embolization beads are applicable to treat: hemorrhage(such as hemorrhage associated with pelvic fracture).

In exemplary embodiments of the present invention, there is provided amethod of treating a condition or disease, using the embolization beadsof the invention. A composition including the embolization beads, whichis for example, administered to a patient in need of an embolizationtherapy having a tumor, for instance a hepatocellular carcinoma, isfirstly prepared. The embolization beads may be administered alone oralong (usually after) administration of a composition including atherapeutic agent (e.g. chemotherapeutics). The embolization beads maybe administered when bound to a chemotherapeutic agent. It is oftendesirable for the suspension to be mixed prior to delivery with animaging agent such as a conventional radio-opaque agent.

The compositions for administration are thus prepared according to thetherapy of interest. The embolization beads may be loaded with theappropriate dose of a therapeutic agent just prior to administration ormay be preloaded and ready for immediate use. When the embolizationbeads are coated with a therapeutic agent just prior to administration,the appropriate dose of the therapeutic agent, may be dissolved inadequate solution, and is then mixed with a suitable amount of beads.The pharmaceutical composition containing the therapeutic agent bound toembolization beads may allow a fast loading (about 1-2 h incubation) anda loading rate of the therapeutic agent into the beads (>99%) able toguarantee an easy administration of therapeutic doses to patients. Thereconstituted therapeutic agent solution must be added to theembolization beads and agitated gently to encourage mixing.

The selection of the size of the embolization beads is based on thevascular target/vessel size.

A delivery catheter/microcatheter must be introduced into the targetvessel according to standard interventional radiology technique. Theembolization must be monitored under fluoroscopic visualization byadding a desired amount of contrast medium (such as a conventionalradio-opaque agent) to a suspension fluid containing the embolizationbeads.

In exemplary embodiments, the embolization beads are slowly injectedinto the delivery catheter/microcatheter under fluoroscopicvisualization while observing the contrast flow rate. Upon completion ofthe treatment, the catheter/microcatheter is removed while maintaininggentle suction so as not to dislodge embolization beads still within thecatheter/microcatheter lumen. The embolic composition as administered tothe patient in need of embolization therapy, may be delivered as asingle one-off dosage. It may be found to be desirable for subsequentdoses of an embolic composition useful in the invention, to be deliveredat a time interval after the previous dose, for instance to embolizenewly formed blood vessels supplying a tumor (e.g. after 4 to 12 weeksfrom the previous treatment).

Reference is now made to FIG. 5 which schematically illustrates anexemplary method of performing an embolization therapy, to treat a livercancer (LC), utilizing a suspension 250 comprising an infusion fluid andembolization beads (e.g., beads 200) of the present invention. Theembolization beads are configured to engage to form, following injectionto a blood vessel (i.e., Hepatic Artery; HA) an aggregated structure(similar or identical to aggregated structure 100 of FIGS. 1 and 2)before or/and during embolization process for forming an embolus withinthe blood vessel, resulting with occluded blood vessel portion 130. Themethod includes, utilization of embolization beads 200 of the invention,but may be applicable to any of the aforementioned embolization beads,in accordance with the embodiments of the invention.

Embolization beads 200 may be used in conjunction with any suitabletechnique or/and procedure of embolization therapy (e.g., TAE, TACE,TARE) and may be introduced within a blood vessel feeding a tumor withany know and suitable catheter. For example, when the beads are providedwith a radioactive isotope the technique is referred to as TARE. Whenthe beads are injected thereafter a chemotherapeutic agentadministration, the technique is referred to as TACE. When a therapeuticagent is coated within the beads, the technique is referred to as DEB(or DEB-TACE), and when the beads are provided without any substance,the technique may be referred to as TAE (or bland embolization).

Typically, for treating liver cancer, a catheter (a thin and flexibletube) is introduced through a small cut in the inner thigh and threadedup into the hepatic artery (HA) in the liver (L). A contrast enhancementmaterial is usually injected into the bloodstream at this time to assistin monitoring the path of the catheter via angiography. Once thecatheter is in positioned as appropriate, embolization beads 200 areinjected into the artery. Once accumulated in the blood vessels,embolization beads 200 are arranged such that protruding portions of afirst embolization bead 200 intermesh with protruding portions of asecond embolization bead 200. Multiple embolization beads 200, thuscreate emboli within boundaries of a blood vessel, blood supply to thetumor is diminished, effecting tumor starvation and necrosis.

Pharmaceutical Compositions Including the Embolization Particulates(Beads)

According to yet another aspect, the present invention also providespharmaceutical compositions including the herein disclosed embolizationbeads, and a pharmaceutical acceptable carrier or excipient.

The term “pharmaceutical composition”, as used herein, encompassesformulated preparations including the herein disclosed embolizationbeads, and one or more pharmaceutically acceptable excipients, diluentsor carriers.

The term “pharmaceutically acceptable”, as used herein, means approvedby a regulatory agency of a federal or a state government or listed in arecognized pharmacopeia for use in humans or animals.

The term “carrier”, as used herein, refers to a diluent, adjuvant,excipient, or vehicle with which the therapeutic is administered. Suchpharmaceutical carriers can be sterile aqueous liquids (e.g., saline, orPBS) or, oils, including those of petroleum, animal, vegetable orsynthetic origin, such as peanut oil, soybean oil, mineral oil, sesameoil and the like. Suitable pharmaceutical excipients include starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, sodium stearate, glycerol monostearate, talc, sodium chloride,dried skim milk, glycerol, propylene, glycol, water, ethanol and thelike. The carrier(s) must be “acceptable” in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipients thereof.

The composition including the embolization beads is typically referredto as a suspension. The suspension may be an infusion suspensioncomprising the beads and an infusion fluid (i.e., pharmaceuticallyacceptable excipients, diluents or carriers). In exemplary embodiments,the embolization beads may have a relatively low specific gravity. Theembolization beads thus benefit from a buoyancy effect for reducedenergy expenditure and prevent sedimentation when provided within apharmaceutical composition or/and when injected within the blood. Inexemplary embodiments, the embolization beads have a density within therange of between about 0.8 and about 2 g/cm³, 0.8 and about 1.8 g/cm³,0.8 and about 1.6 g/cm³, 0.8 and about 1.4 g/cm³, 0.8 and about 1.2g/cm3, between about 0.9 and about 1.1 g/cm3, between about 0.9 andabout 1.0 g/cm3. Each possibility represents a separate embodiment ofthe invention.

The following examples are presented in order to more fully illustratecertain embodiments of the invention. They should in no way, however, beconstrued as limiting the broad scope of the invention. One skilled inthe art can readily devise many variations and modifications of theprinciples disclosed herein without departing from the scope of theinvention.

EXAMPLES Example 1—A Process for Preparing Embolization Beads Capable ofIntermeshing, in Accordance with Embodiments of the Invention

Analytical grade reagents including one or more of: silicon dioxide,calcium carbonate, zinc oxide, magnesium oxide, lanthanum (III) oxide,strontium carbonate, titanium dioxide and sodium carbonate are weighedand homogeneously blended. The blend is then heated to a temperaturewithin the range of from about 1500° to 1600° C. for a time period of 30min to 5 hours. A volume is then injected to a premade cold scaffold ormold having a predetermined shape to thereby form particulates ofembolization beads having customized diameter which may vary to bebetween the ranges of 10 μm and 1,000 μm.

The formed particulates are then extracted from the mold. The formedparticulates may then be sterilized (for example, using 30 kGy gammairradiation). In exemplary embodiments, the embolization beads aretreated to incorporate a therapeutic agent within holes or a concavityshape that may be included within the protruding portions of the beads.Holes may be patched by ejector pins.

Also optionally, a radioactive isotope may be impregnated onto theembolization beads.

Example 2—Beads Coating with a Therapeutic Agent

Beads prepared as exemplified in Example 1 are coated with a desiredtherapeutic agent as follows: a therapeutic agent (e.g., doxorubicin) isdissolving in an appropriate solvent and admixed with the beads. Thesystem is allowed for incubation for up to 24 hours under gentleagitation and at a temperature of 37° C. The coated beads may then bedried by an appropriate technique such as by freeze-drying.

Example 3—Therapeutic Agent Release Analysis

A beads suspension is inserted to a pre-swollen dialysis bag, thedialysis bag is clamped at both ends, and transferred to a containercontaining PBS. The system is allowed for incubation under gentleagitation at a temperature of 37° C. and a sample f is taken at varioustime intervals to evaluate drug release under spectrophotometer.

Example 4—Beads Incorporation with a Radioisotope

Beads are incubated in a solution including a radioisotope for up to 24hours. Following incubation, beads are washed twice with saline or PBS.Beads are centrifuged for 60 seconds at 6000 rpm, and the supernatant isremoved. Each sample is then washed with 1 mL of saline and agitated forseconds. Final solutions are disposed in vials with 20 mL ofscintillation liquid each, and counted for activity by a liquidscintillation analyzer.

Each of the following terms written in singular grammatical form: ‘a’,‘an’, and ‘the’, as used herein, means ‘at least one’, or ‘one or more’.Use of the phrase ‘one or more’ herein does not alter this intendedmeaning of ‘a’, ‘an’, or ‘the’. Accordingly, the terms ‘a’, ‘an’, and‘the’, as used herein, may also refer to, and encompass, a plurality ofthe stated entity or object, unless otherwise specifically defined orstated herein, or, unless the context clearly dictates otherwise. Forexample, the phrases: ‘a unit’, ‘a device’, ‘an assembly’, ‘amechanism’, ‘a component’, ‘an element’, and ‘a step or procedure’, asused herein, may also refer to, and encompass, a plurality of units, aplurality of devices, a plurality of assemblies, a plurality ofmechanisms, a plurality of components, a plurality of elements, and, aplurality of steps or procedures, respectively.

Each of the following terms: ‘includes’, ‘including’, ‘has’, ‘having’,‘comprises’, and ‘comprising’, and, their linguistic/grammaticalvariants, derivatives, or/and conjugates, as used herein, means‘including, but not limited to’, and is to be taken as specifying thestated component(s), feature(s), characteristic(s), parameter(s),integer(s), or step(s), and does not preclude addition of one or moreadditional component(s), feature(s), characteristic(s), parameter(s),integer(s), step(s), or groups thereof. Each of these terms isconsidered equivalent in meaning to the phrase ‘consisting essentiallyof’.

Each of the phrases ‘consisting of’ and ‘consists of’, as used herein,means ‘including and limited to’.

The phrase ‘consisting essentially of’, as used herein, means that thestated entity or item (system, system unit, system sub-unit, device,assembly, sub-assembly, mechanism, structure, component, element, or,peripheral equipment, utility, accessory, or material, method orprocess, step or procedure, sub-step or sub-procedure), which is anentirety or part of an exemplary embodiment of the disclosed invention,or/and which is used for implementing an exemplary embodiment of thedisclosed invention, may include at least one additional ‘feature orcharacteristic’ being a system unit, system sub-unit, device, assembly,sub-assembly, mechanism, structure, component, or element, or,peripheral equipment, utility, accessory, or material, step orprocedure, sub-step or sub-procedure), but only if each such additional‘feature or characteristic’ does not materially alter the basic noveland inventive characteristics or special technical features, of theclaimed entity or item.

The term ‘method’, as used herein, refers to steps, procedures, manners,means, or/and techniques, for accomplishing a given task including, butnot limited to, those steps, procedures, manners, means, or/andtechniques, either known to, or readily developed from known steps,procedures, manners, means, or/and techniques, by practitioners in therelevant field(s) of the disclosed invention.

Throughout this disclosure, a numerical value of a parameter, feature,characteristic, object, or dimension, may be stated or described interms of a numerical range format. Such a numerical range format, asused herein, illustrates implementation of some exemplary embodiments ofthe invention, and does not inflexibly limit the scope of the exemplaryembodiments of the invention. Accordingly, a stated or describednumerical range also refers to, and encompasses, all possible sub-rangesand individual numerical values (where a numerical value may beexpressed as a whole, integral, or fractional number) within that statedor described numerical range. For example, a stated or describednumerical range ‘from 1 to 6’ also refers to, and encompasses, allpossible sub-ranges, such as ‘from 1 to 3’, ‘from 1 to 4’, ‘from 1 to5’, ‘from 2 to 4’, ‘from 2 to 6’, ‘from 3 to 6’, etc., and individualnumerical values, such as ‘1’, ‘1.3’, ‘2’, ‘2.8’, ‘3’, ‘3.5’, ‘4’,‘4.6’, ‘5’, ‘5.2’, and ‘6’, within the stated or described numericalrange of ‘from 1 to 6’. This applies regardless of the numericalbreadth, extent, or size, of the stated or described numerical range.

Moreover, for stating or describing a numerical range, the phrase ‘in arange of between about a first numerical value and about a secondnumerical value’, is considered equivalent to, and meaning the same as,the phrase ‘in a range of from about a first numerical value to about asecond numerical value’, and, thus, the two equivalently meaning phrasesmay be used interchangeably.

The term ‘about’, as used herein, refers to ±10% of the stated numericalvalue.

It is to be fully understood that certain aspects, characteristics, andfeatures, of the invention, which are, for clarity, illustrativelydescribed and presented in the context or format of a plurality ofseparate embodiments, may also be illustratively described and presentedin any suitable combination or sub-combination in the context or formatof a single embodiment. Conversely, various aspects, characteristics,and features, of the invention which are illustratively described andpresented in combination or sub-combination in the context or format ofa single embodiment, may also be illustratively described and presentedin the context or format of a plurality of separate embodiments.

Although the invention has been described in conjunction with specificembodiments thereof, it is evident that many alternatives, modificationsand variations will be apparent to those skilled in the art.Accordingly, it is intended to embrace all such alternatives,modifications and variations that fall within the spirit and broad scopeof the appended claims.

All publications, patents and patent applications mentioned in thisspecification are herein incorporated in their entirety by referenceinto the specification, to the same extent as if each individualpublication, patent or patent application was specifically andindividually indicated to be incorporated herein by reference. Inaddition, citation or identification of any reference in thisapplication shall not be construed as an admission that such referenceis available as prior art to the present invention. To the extent thatsection headings are used, they should not be construed as necessarilylimiting.

What is claimed is:
 1. A composition comprising a plurality of beads,each of said plurality of beads having a permanent shape, furnishing thebeads with a capability to resist aggregation during flow and to promoteaggregation upon cessation of flow.
 2. The composition of claim 1,wherein said plurality of beads are configured to resist and/ordissipate forces generated by, or originating from, fluid flow during anembolization procedure.
 3. The composition of claim 1, wherein each ofsaid plurality of beads are embolization beads.
 4. The composition ofclaim 1, wherein each of said plurality of beads have a tetrahedron ortetrahedron-like shape.
 5. The composition of claim 1, wherein each ofsaid plurality of beads have a tetrapod-like shape.
 6. The compositionof claim 1, each of said plurality of beads having a density within therange of between about 0.8 and about 1.6 g/cm³.
 7. The composition ofclaim 1, wherein said plurality of beads comprises holes filled with atherapeutic agent.
 8. The composition of claim 1, wherein said pluralityof beads are made of glass, metal, polymer, or a combination thereof. 9.The composition of claim 1, wherein each of said plurality of beads hasa maximal diameter in a range of between about 5 microns and about 1,000microns.
 10. The composition of claim 9, wherein each of said pluralityof beads has a maximal diameter within the range of 5 microns and 500microns.
 11. The composition of claim 10, wherein each of said pluralityof beads has a maximal diameter within the range of between about 5microns and about 100 microns.
 12. The composition of claim 1, furthercomprising a pharmaceutically acceptable excipient or carrier.
 13. Thecomposition of claim 1, further comprising a contrasting agent or atherapeutic agent.
 14. The composition of claim 13, wherein saidcontrasting agent is selected from the group consisting of tantalum,tantalum oxide, and barium sulfate.
 15. The composition of claim 13,wherein said therapeutic agent is a chemotherapeutic agent.
 16. A methodfor embolizing or occluding a blood vessel in a subject, the methodcomprising: injecting into the blood vessel a sufficient amount of thecomposition according to claim 1, wherein the permanent shape of theplurality of beads prevent aggregation of the beads during injection andpromote upon delivery to the blood vessel.
 17. The method of claim 16,wherein the blood vessel feeds a tumor or an arteriovenous malformation.18. The method of claim 16 for treating and/or ameliorating a tumor oran arteriovenous malformation.